Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline Radicals to α,β-Unsaturated Enones via Photoredox Catalysis

Article abstract of DOI:10.1002/adsc.201400702

We have developed an intermolecular conjugate addition of 3a-pyrroloindoline/furoindoline radicals to α,β-unsaturated enones, through visible-light photoredox catalysis. Ir(ppy)₂(dtbbpy) PF₆ was found to be an effective promoter to initiate this reaction from readily available 3a-bromopyrroloindolines/furoindolines. This method was exploited to prepare a series of indole terpenoid-like compounds of potential biological interest.

Full text of DOI:10.1002/adsc.201400702

UPDATES
DOI: 10.1002/adsc.201400702
Intermolecular Conjugate Addition of Pyrroloindoline and
Furoindoline Radicals to a,b-Unsaturated Enones via
Photoredox Catalysis
Shupeng Zhou,+a Deliang Zhang,+a Yu Sun,a Ruofan Li,a Wenhao Zhang,a
and Ang Lia,*
a
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5125; e-mail: ali@sioc.ac.cn
+
S.Z. and D.Z. contributed equally to this work.
Received: July 18, 2014; Revised: August 14, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400702.
Abstract: We have developed an intermolecular
conjugate addition of 3a-pyrroloindoline/furoindo-
line radicals to a,b-unsaturated enones, through
Recently, photoredox catalysis has emerged as
a useful tool for controllable radical chemistry.[3] As
demonstrated in some cases, the manner of the radical
initiation and termination in a photoredox catalytic
cycle overcomes some disadvantaged of conventional
radical chemistry; therefore, visible-light photoredox
catalysis represents not only a “green” alternative to
traditional radical protocols, but also a new avenue
for the discovery of synthetically useful reactions.[4] In
the total synthesis of drimentine A (1, Figure 1), we
took advantage of photoredox catalysis to effect a rad-
visible-light photoredox catalysis. IrACHTNUTRGENNUG(ppy)2ACHTUNGTRENN(UGN dtbbpy)
PF6 was found to be an effective promoter to ini-
tiate this reaction from readily available 3a-bromo-
pyrroloindolines/furoindolines. This method was ex-
ploited to prepare a series of indole terpenoid-like
compounds of potential biological interest.
Keywords: alkaloid-terpenoid hybrids; conjugate
addition; furoindolines; photoredox catalysis; pyr-
roloindolines
À
ical 1,4-addition as the key C C bond (highlighted in
bold in Figure 1) forming reaction.[5] Herein, we
report the photocatalyzed intermolecular conjugate
addition of 3a-pyrroloindoline/furoindoline radicals to
a,b-unsaturated enones,[6,7] as a general and facile
access to a series of indole terpenoid-like structures.
We first investigated the conditions for the conju-
À
The conjugate addition is a powerful C C bond form-
ing reaction.[1] From the stereochemical perspective, gate addition using enone 2 and racemic 3a-bromo
this reaction may provide the opportunity of generat- pyrroloindoline 3 as the substrates (Table 1). Conven-
ing up to three stereogenic centers (two from the ac- tional radical conditions (AlBN or Et3B/O2) afforded
ceptor and one from the donor). Carbanions, elec-
tron-rich p systems, organometallic species, and free
radicals have been widely explored as the donors for
conjugate addition reactions, which have found re-
markable applications in the synthesis of natural
products and pharmaceutically interesting com-
pounds. Notably, the addition of a tertiary carbon to
an electron-deficient unsaturated system is rather lim-
ited because of the steric and reactivity problems. In
principle, a free radical approach is a suitable means
to overcome both problems; however, the intermolec-
ular radical 1,4-addition sometimes suffers from
severe side reactions, such as the reductive quench,
Figure 1. The structure of pyrroloindoline natural product
drimentine A.
due to the high reactivity of the radical species.[2]
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Shupeng Zhou et al.
Table 1. Conditions for the intermolecular conjugate addi-
tion.
phor-derived enone 2d served as a good acceptor for
the radical addition, and the product 4d was obtained
in 94% yield as a mixture of C-3 diastereomers (1.8:1
dr). Enones 2e–j, derived from (+)-dehydroandroster-
one, (+)-epiandrosterone, (+)-estrone, (+)-sclareo-
lide, and (À)-carvone, respectively, also smoothly re-
acted with the optically active 3a-bromopyrroloindo-
line (entries 5–10). For entries 5, 6, 8, and 9, the ad-
ducts 4e, f, h, i were isolated as single diastereomers,
respectively. The structures of 4h and 4i were assigned
according to the X-ray crystallographic analysis of an
analogue reported in the drimentine synthesis,[5] and
the relative configuration of 4f was verified by NOE
studies (see the Supporting Information). In some
other cases, the low diastereoselectivity at the carbon-
yl a position could be attributable to the weak steric
bias of the particular ketone moieties, which may not
Entry Conditions[a]
Yield
1
2
3
4
AIBN, Bu3SnH, toluene, 808C
8%
13%
<2%
Et3B, O2, Bu3SnH, THF, 228C
Bu3SnH (syringe pump), toluene, 808C[b]
À
diminish the general advantage of this C C bond
[Ru
Et3N, DMF, 228C[c]
[Ir(bpy)2A(dtbbpy)]PF6 (2.5 mol%), blue LED, 90%
Et3N, DMF, 228C[c]
ACHTUNGTRENNUNG(bpy)3]Cl2·6 H2O (2.5 mol%), blue LED, 11%
forming process. Interestingly, for entry 7, a 1.6:1 dr
at C-16 of 4g was observed, despite the remarkable
structural similarity between 4g and 4e. This ratio can
be enhanced to 5:1 by treatment of the isolated prod-
uct with DBU at 808C. The C-16 configuration of 4e
and the major epimer of 4g was elucidated based on
the comparison with that of the thermodynamically
favorable C-16 substituted estrone derivative.[8] En-
5
A
CHTUNGTRENNUNG
[a]
[b]
[c]
2.0 equiv. of 2.
10.0 equiv. of 2.
2.0 equiv. of Et3N.
trace amounts of the desired product 4 (entries 1 and tries 9 and 10 show the selectivity of the 1,1- over 1,2-
2).[7] The reductive debromination of 3 was very rapid disubstituted enone in the conjugate addition. It
under these conditions. Slow addition of a highly di- should be noted that endocyclic and linear enones
luted solution of Bu3SnH in benzene via a syringe with the 1,2-disubstitution pattern do not participate
pump, which gave a reasonable yield of the conjugate in this reaction. The a,b-unsaturated aldehyde, ester,
adduct in the synthesis of drimentine A, proved to be and lactone with exocyclic C=C bonds (e.g., 2k–m)
fruitless with this pair of substrates (entry 3). It may are good acceptors for the conjugate addition (en-
be attributable to the lability of 2 under thermal con- tries 11–13).
ditions. Photoredox catalyst Ru
G
With the above results, we have demonstrated the
employed by Stephenson and co-workers for initiating power of the intermolecular conjugate addition for
radicals from structurally similar 3a-bromopyrroloin- forging together two biologically privileged motifs,
dolines.[4c,e] However, in our case, it only provided the pyrroloindoline and steroid. This strategy was fur-
11% of 4 when Et3N was used as a reductant ther applied to the synthesis of a pyrroloindoline-ole-
(entry 4). In this case, both 2 and 3 were partially re- anolic acid hybrid,[9] as shown in Scheme 1. Oleanolic
covered. To our delight, [IrACHTNUTRGENNUG(bpy)2ACHTUNGTREN(NGUN dtbbpy)]PF6 was acid methyl ester (5) was subjected to a two-step se-
found to be an effective catalyst and led to a satisfac- quence (DMP oxidation followed by exposure to
tory yield of 4 (90%) under the irradiation of blue Et3N and Eschenmoserꢀs salt), to give enone 6 in 78%
LEDs (lmax =454 nm). It should be noted that 4 was overall yield. The conjugate addition proceeded well
obtained as a 1.4:1 diastereomeric mixture at C-2, with the substrates 5 and 7, to deliver a complex alka-
and the stereochemistry of the pyrroloindoline motif loid-terpenoid hybrid 8 (1.5:1 dr at C-18) in 87%
was retained through the radical process because of yield. This compound may serve as a versatile inter-
its structurally rigidity.
mediate to derive the corresponding diketopipera-
We explored the scope of the conjugate addition zines for biological studies.
with a variety of electron-deficient olefins (2a–m) and
In Scheme 2 is depicted a postulated mechanism
two synthetically important pyrroloindoline/furoindo- for the photocatalyzed conjugate addition. The aro-
line bromides. Conjugate adducts 4a–m were obtained matic moiety of 3 is reduced by an Ir(II) species, and
À
in good to excellent yields (Table 2). Arene-fused the mesolysis of the benzylic C Br bond proceeds to
cyclic enones 2a–c proved to be suitable substrates for generate a pyrroloindoline radical 9, which then at-
this reaction (entries 1–3). A series of a,b-unsaturated tacks enone 2, the resultant a-carbonyl radical 10 is
enones 2d–j arising from naturally occurring ketones further reduced by a reactive species (e.g., Et3N radi-
were then tested. As shown in entry 4, a (+)-cam- cal cation).[10] The reductant is generated and then
2
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Intermolecular Conjugate Addition of Pyrroloindoline and Furoindoline
Table 2. Intermolecular conjugate addition of 3a-pyrroloindoline/furoindoline radicals to a,b-unsaturated enones.[a]
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[a]
[IrACHTUNGTRENNUNG(bpy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 (2.5 mol%), enone (2.0 equiv.), Et3N (2.0 equiv.), blue LEDs (lmax =454 nm), DMF, 228C, 16 h.
Scheme 1. Synthesis of
hybrid.
a
pyrroloindoline-oleanolic acid
Scheme 2. A postulated mechanism of the photocatalyzed
radical conjugate addition.
consumed in the catalytic cycle, and thus maintains a facile and efficient access to a collection of structur-
a very low concentration, which suppresses the severe ally complex alkaloid-terpenoid hybrids of potential
debrominative side-reaction of 3 that is often ob- biological interest.
served under conventional radical conditions. In this
particular case, the stereochemistry at the carbonyl
a position of the product 4 cannot be well controlled
due to the weak stereochemical effect from the pyrro-
Experimental Section
loindoline motif. As for 4e, f, h, and i, the hydrogen
source may prefer to approach the enol radical from
the axial or pseudo-axial direction to develop less
steric congestion, and therefore results in a high level
of diastereoselectivity.
In summary, we have developed an intermolecular
radical conjugate addition via visible-light photoredox
General Procedure for the Intermolecular Conjugate
Addition
To a stirred solution of 3a-bromopyrroloindoline or -furoin-
doline (0.500 mmol) and a,b-unsaturated enone (1.00 mmol)
in DMF (2.0 mL) were sequentially added [Ir
ACHTUNGTRENNUNG(ppy)2
AHCTUNGTRE(NGNUN dtbbpy)]PF6 (11.4 mg, 0.0125 mmol) and Et3N (102 mg,
140 mL, 1.00 mmol) at 228C. The resulting mixture was
stirred at that temperature for 16 h upon the irradiation of
a blue LED (lmax =454 nm, 20 W). After removal of the sol-
catalysis.
3a-Bromopyrroloindolines/-furoindolines
and a,b-unsaturated enones were employed as the
substrates for this reaction. This method provides vent under vacuum, the residue was purified by flash
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column chromatography with EtOAc/petroleum ether to
give the conjugate adduct.
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Acknowledgements
We thank Prof. Wen-Jing Xiao and Dr. David Edmonds for
helpful discussions and Wenmin Wu for mass spectrometric
assistance. Financial support was provided by Ministry of
Science & Technology (2013CB836900), National Natural
Science Foundation of China (21290180, 21172235, and
21222202), Pujiang program (12PJ1410800), and Chinese
Academy of Sciences.
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UPDATES
Intermolecular Conjugate Addition of Pyrroloindoline and
Furoindoline Radicals to a,b-Unsaturated Enones via
Photoredox Catalysis
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Shupeng Zhou, Deliang Zhang, Yu Sun, Ruofan Li,
Wenhao Zhang, Ang Li*
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